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Abstract: Background. Treatment of malignant mesothelioma (MM) still relies on chemotherapy with cisplatin in combination with pemetrexed or other drugs. Studies indicate that hypoxic conditions within tumour tissue may reduce responsiveness to cisplatin-based chemotherapy. Hypoxia-inducible factors (HIF) play an important role in regulation of cellular adaptation to hypoxia. The aim of our study was to investigate single nucleotide polymorphisms (SNPs) in the HIF1A gene coding for the regulatory alpha subunit (HIF-1A) and their role in the response to chemotherapy in patients with MM. Patients and methods. Our retrospective genetic association study included 234 patients with MM, who were treated with a combination of cisplatin/pemetrexed or cisplatin/gemcitabine at the Institute of Oncology Ljubljana between January 2001 and September 2018. Selected HIF1A SNPs (rs1154965, rs11549467, and rs2057482) were genotyped using the competitive allele-specific polymerase chain reaction (KASP). Additionally, we used a TaqMan assay for independent confirmation of rs11549465 genotyping results. The impact of the SNPs on response to chemotherapy was analysed using logistic regression. For survival analysis, we used the Kaplan-Meier method and Cox regression. Results. In heterozygotes with the HIF1A rs11549465 CT genotype, response to chemotherapy was significantly worse compared to homozygotes with the CC genotype, but only after adjustment for weight loss and CRP (ROadj = 0.37; 95% CI = 0.14–0.97; Padj = 0.044). HIF1A rs11549467 and rs2057482 were not associated with response to chemotherapy (all P > 0.05). None of the investigated SNPs were associated with progression-free survival or overall survival (all P > 0.05). Conclusions. Among the investigated HIF1A SNPs, only rs11549465 has showed association with a worse response to chemotherapy after the adjustment for clinical parameters. The findings of this study have improved our understanding of the role of HIF1A polymorphisms in MM and may offer valuable insights into their impact on other cancers as well.
Keywords: malignant mesothelioma, chemotherapy, polymorphism
Published in DiRROS: 10.12.2025; Views: 379; Downloads: 79
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Abstract: We investigated the impact of genetic polymorphisms in the GLP1R and SLC5A2 genes on the response to treatment with glucagon-like peptide-1 receptor (GLP-1R) agonists and sodium-glucose co-transporter-2 (SLGT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) in everyday clinical practice.In our prospective interventional cohort open-label real-world genetic association study (DRKS-ID: DRKS00034478, https://drks.de/search/en/trial/DRKS00034478), we enrolled 161 clinically well-defined T2DM patients who received SGLT2 inhibitors and/or GLP-1R agonists alongside other medications for 3-6 months. The study's primary outcomes (HbA1c, body mass, and blood pressure) were measured before the treatment and at the follow-up at 3-6 months. GLP1R rs6923761, rs10305420, and SLC5A2 rs9934336 genotypes were determined by competitive allelespecific polymerase chain reaction. In patients receiving GLP-1R agonists, we analyzed the effect of GLP1R polymorphisms on the patients' response to treatment, while in patients receiving SGLT2 inhibitors, we analyzed the impact of the SLC5A2 polymorphism on the treatment effect.Treatment with prescribed antihyperglycemic drugs improved all primary outcomes (p < 0.050). The normal GLP1R rs6923761 G allele was associated with a greater reduction in HbA1c with GLP-1R agonists treatment than the polymorphic A allele in the dominant model (p = 0.029).The prevalent polymorphic A allele of GLP1R rs6923761 polymorphism was associated with the clinically relevant lower glycemic response to GLP-1R agonists. The described impact extends to everyday clinical practice, indicating that knowledge of these genetic polymorphisms could facilitate the development of targeted and personalized therapy in managing T2DM.
Keywords: polymorphism, type 2 diabetes, treatment response
Published in DiRROS: 17.11.2025; Views: 264; Downloads: 143
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Abstract: Extracellular vesicle-bound DNA (evDNA) is an understudied extracellular vesicle (EV) cargo, particularly in cancer-unrelated research. Although evDNA has been detected in urine, little is known about its characteristics, localization, and biomarker potential for kidney pathologies. To address this, we enriched EVs from urine of well-characterized kidney transplant recipients undergoing allograft biopsy, characterized their evDNA and its association to allograft injury. The SEC-based method enriched pure EVs from urine of kidney transplant recipients, regardless of the allograft injury. Urinary evDNA represented up to 29.2 ± 8% (mean ± SD) of cell-free DNA (cfDNA) and correlated with cfDNA in several characteristics but was less fragmented (P < 0.001). Importantly, using DNase treatment and immunogold labelling TEM, we demonstrated that evDNA was bound to the surface of urinary EVs. Normalised evDNA yield (P = 0.042) and evDNA copy number (P = 0.027) significantly differed between patients with normal histology, rejection injury and non-rejection injury, the later groups having significantly larger uEVs (mean diameter, P = 0.045) and more DNA bound per uEV. ddDNA is detectable in uEV samples of kidney allograft recipients, but its quantity is highly variable. In a proof-of-principle study, several evDNA characteristics correlated with clinical and histological parameters (P = 0.040), supporting that the potential of evDNA as a biomarker for kidney allograft injury should be further investigated.
Keywords: DNA, donor-derived DNA, extracellular vesicles
Published in DiRROS: 26.02.2025; Views: 762; Downloads: 600
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Abstract: Background. Asbestos exposure is associated with different asbestos-related diseases, including malignant meso-thelioma (MM). MM diagnosis is confirmed with immunohistochemical analysis of several markers, including calretinin. Increased circulating calretinin was also observed in MM. The aim of the study was to determine if CALB2 polymor-phisms or polymorphisms in genes that can regulate calretinin expression are associated with serum calretinin levels or MM susceptibility.Subjects and methods. The study included 288 MM patients and 616 occupationally asbestos-exposed subjects without MM (153 with asbestosis, 380 with pleural plaques and 83 without asbestos-related disease). Subjects were genotyped for seven polymorphisms in CALB2, E2F2, MIR335, NRF1 and SEPTIN7 genes using competitive allele-specific polymerase chain reaction (PCR). Serum calretinin was determined with ELISA in 545 subjects. Nonparametric tests, logistic regression and receiver operating characteristic (ROC) curve analysis were used for statistical analysis.Results. Carriers of at least one polymorphic CALB2 rs889704 allele had lower calretinin levels (P = 0.036). Carriers of two polymorphic MIR335 rs3807348 alleles had higher calretinin (P = 0.027), while carriers of at least one polymorphic NRF1 rs13241028 allele had lower calretinin levels (P = 0.034) in subjects without MM. Carriers of two polymorphic E2F2rs2075995 alleles were less likely to develop MM (odds ratio [OR] = 0.64, 95% confidence interval [CI] = 0.43-0.96, P = 0.032), but the association was no longer significant after adjustment for age (P = 0.093). Optimal serum calretinin cut-off values differentiating MM patients from other subjects differed according to CALB2, NRF1, E2F2, and MIR335genotypes.Conclusions. The results of presented study suggest that genetic variability could influence serum calretinin levels. These findings could contribute to a better understanding of calretinin regulation and potentially to earlier MM diag-nosis.
Keywords: malignant mesothelioma, calretinin, CALB2, asbestos-related disease, polymorphism
Published in DiRROS: 26.07.2024; Views: 1229; Downloads: 567
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Abstract: The study investigated the influence of GCLC, GCLM, GSTM1, GSTT1 and GSTP1 polymorphisms, as well as the influence of interactions between polymorphism and interactions between polymorphisms and asbestos exposure, on the risk of developing pleural plaques, asbestosis and malignant mesothelioma (MM). Subjects and methods. The cross sectional study included 940 asbestos-exposed subjects, among them 390 subjects with pleural plaques, 147 subjects with asbestosis, 225 subjects with MM and 178 subjects with no asbestos-related disease. GCLC rs17883901, GCLM rs41303970, GSTM1 null, GSTT1 null, GSTP1 rs1695 and GSTP1 rs1138272 genotypes were determined using PCR based methods. In statistical analysis, logistic regression was used. Results. GSTT1 null genotype was associated with the decreased risk for pleural plaques (OR = 0.63; 95% CI = 0.40% 0.98; p = 0.026) and asbestosis (OR = 0.51; 95% CI = 0.28%0.93; p = 0.028), but not for MM. A positive association was found between GSTP1 rs1695 AG + GG vs. AA genotypes for MM when compared to pleural plaques (OR = 1.39; 95% CI = 1.00%1.94; p = 0.049). The interactions between different polymorphisms showed no significant influence on the risk of investigated asbestos-related diseases. The interaction between GSTT1 null polymorphism and asbestos exposure decreased the MM risk (OR = 0.17; 95% CI = 0.03%0.85; p = 0.031). Conclusions. Our findings suggest that GSTT1 null genotype may be associated with a decreased risk for pleural plaques and asbestosis, may modify the association between asbestos exposure and MM and may consequently act protectively on MM risk. This study also revealed a protective effect of the interaction between GSTP1 rs1695 polymorphism and asbestos exposure on MM risk.
Keywords: polymorphisms, glutathione-related genes, asbestos, malignant mesothelioma
Published in DiRROS: 19.07.2024; Views: 1043; Downloads: 336
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